Modelling acrylamide acute neurotoxicity in zebrafish larvae

Prats, Eva; Gómez‐Canela, Cristian; Ben-Lulu, Shani; Ziv, Tamar; Padrós, Francesc; Tornero, Daniel; García-Reyero, Natàlia; Tauler, Romà; Admon, Arie; Raldúa, Demetrio

doi:10.1038/s41598-017-14460-3

Cited by 45 publications

(42 citation statements)

References 60 publications

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“…These studies revealed specific behavioral, transcriptomic and metabolic markers compatible with the known effects of AA neurotoxicity in humans and rodents [7][8][9] . These results pointed to the nervous system as an early target of AA toxicity, indicated by changes in the adult brain proteome and transcriptome, as well as in the neurotransmitter systems, and alterations in the presynaptic vesicles of larval motoneurons [7][8][9] . However, these data did not allow the identification of the molecular pathways implicated in the observed effects, nor did they define the mechanistic relationships linking these molecular events to the whole-animal toxidrome.…”

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confidence: 75%

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confidence: 99%

“…Within a project to characterize a zebrafish model for studying neurotoxic effects of AA and other neurotoxicants, we recently studied the effects of AA acute exposure in zebrafish adults 7,8 and larvae 9 . These studies revealed specific behavioral, transcriptomic and metabolic markers compatible with the known effects of AA neurotoxicity in humans and rodents [7][8][9] . These results pointed to the nervous system as an early target of AA toxicity, indicated by changes in the adult brain proteome and transcriptome, as well as in the neurotransmitter systems, and alterations in the presynaptic vesicles of larval motoneurons [7][8][9] .…”

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confidence: 99%

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Targeting redox metabolism: the perfect storm induced by acrylamide poisoning in the brain

Raldúa

Casado

Prats

et al. 2020

Sci Rep

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Exposure to acrylamide may lead to different neurotoxic effects in humans and in experimental animals. to gain insights into this poorly understood type of neurotoxicological damage, we used a multi-omic approach to characterize the molecular changes occurring in the zebrafish brain exposed to acrylamide at metabolite, transcript and protein levels. We detected the formation of acrylamide adducts with thiol groups from both metabolites and protein residues, leading to a quasi-complete depletion of glutathione and to the inactivation of different components of the thioredoxin system. We propose that the combined loss-of-function of both redox metabolism-related systems configure a perfect storm that explains many acrylamide neurotoxic effects, like the dysregulation of genes related to microtubules, presynaptic vesicle alteration, and behavioral alterations. We consider that our mechanistical approach may help developing new treatments against the neurotoxic effects of acrylamide and of other neurotoxicants that may share its toxic mode of action.

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confidence: 75%

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confidence: 99%

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confidence: 99%

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Targeting redox metabolism: the perfect storm induced by acrylamide poisoning in the brain

Raldúa

Casado

Prats

et al. 2020

Sci Rep

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“…As the primary dose‐limiting side effect of bortezomib is peripheral neuropathy, we further characterized our lead compound 27 in a Danio rerio embryo escape response assay established in our group similar to reported approaches . For the determination of neurotoxic effects embryos were dechorionated at 24 hpf and treated with two escalating doses of bortezomib 1 and ketoamide 27 (25 μM, 50 μM) for 24 h to 72 h. Subsequently, escape responses of surviving embryos were analyzed at 96 hpf evoked by touch stimulation and tracked with a high‐speed camera at 500 fps to allow quantification of embryo movement characteristics (Figure a).…”

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confidence: 99%

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

et al. 2019

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The ubiquitin‐proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly‐reversibly binding boronates, optimization of novel covalent‐reversibly binding warheads remains largely unattended. We previously reported α‐ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy‐substituted α‐ketoamides combining the structure‐activity relationships from the primed and the non‐primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3‐phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time‐dependent inhibition of cellular substrate conversion. Furthermore, the α‐ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity.

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“…It exhibited the alterations of motor function and presynaptic nerve terminals at the neuromuscular junction. Analysis of neurotransmitter profile showed a significant effect on cholinergic and dopaminergic systems due to the chronic effects of ACR [25]. Faria et al [11] reported that the development of psychological disorders was observed in response to ACR exposure.…”

Section: Acr and Brainmentioning

confidence: 99%

Review on Chronic Exposure of Acrylamide Causes a Neurotoxicity Risk

Maddu

Begum

2018

INNOCS Theranos Pharmco Sci

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The exposure and inhalation of acrylamide (ACR) are not safe to the human health leading to the potential neurotoxicity. ACR is widely used in biochemical techniques and highly occurs in processing foods such as potato chips prepared at high temperatures. ACR is formed from reducing sugars and asparagine through the Maillard reaction. It exerts various harmful and toxic effects such as neurotoxicity both in humans and animal studies. The extensive damage of synaptic proteins, the formation of ACR-DNA adducts, degeneration of motor neurons, neurofilament reduction, are the most common neurological symptoms. The main metabolite of ACR metabolism is glycidamide, and it causes harmful effects as same as ACR. The main purpose of this study is to analyze the neurotoxic effects of ACR on various regions of the brain and its different mechanistic pathways that are involved in ACR neurotoxicity. The consumption of ACR-containing foods and its exposure are reduced by the human, leading to the reduction of toxic effects associated with ACR.

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Modelling acrylamide acute neurotoxicity in zebrafish larvae

Cited by 45 publications

References 60 publications

Targeting redox metabolism: the perfect storm induced by acrylamide poisoning in the brain

Targeting redox metabolism: the perfect storm induced by acrylamide poisoning in the brain

Cell‐Based Optimization of Covalent Reversible Ketoamide Inhibitors Bridging the Unprimed to the Primed Site of the Proteasome β5 Subunit

Review on Chronic Exposure of Acrylamide Causes a Neurotoxicity Risk

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